The regulation of cell division (mitosis) is of critical importance to the normal growth and development of a multicellular organism, as well as the homeostatic maintenance of tissues, and the ability of certain cell types to respond appropriately to environmental cues.
Loss of control of normal cell proliferation rate occurs when the “checkpoints” of cell division fail to function normally. This occurs when normal cells acquire basic genetic damage through somatic mutations to key regulatory genes or through genetic inheritance, thus becoming “initiated” cells. The genetic abnormalities in initiated cells lead to altered gene expression and altered cell behaviour.
The initiated cells may undergo clonal expansion and act as a site for additional genetic alteration. Cell proliferation acts to push clonal expansion. Should further genetic damage occur, the initiated cells can eventually accumulate sufficient genetic damage to cell-cycle regulatory genes to form neoplastic cells, resulting in a neoplastic cell mass or neoplasm.
Neoplasms are generally classified as benign or malignant. Benign tumours proliferate locally and are composed of differentiated cells resembling those of the tissue of origin, the edge of the tumour remaining well defined, and usually encapsulated. Malignant neoplasms (classically termed “cancers”) are not encapsulated and their edges are ill-defined, the cells are also less well differentiated than the cells of origin, and show increased mitotic activity.
Localised, chronic irritation or inflammation can also cause cells to divide abnormally, resulting in abnormal growths or cellular masses, or tumours. Reactive cellular growth responses to clearly defined, chronic irritant stimulation are described as metaplasias. In dysplasias, there is a disorganisation of the pattern of squamous epithelium in tissues such as the skin, oesophagus and uterus in response to chronic irritation or inflammation.
Numerous compounds are commercially available as chemotherapeutic agents for destruction of abnormally proliferating cells in benign and malignant neoplasias, dyplasias and metaplasias. Predicting the responsiveness of a given tumour-related disease type to a particular drug is difficult, as each disease type is different and may respond to different treatments. Generally, clinical treatment of cancer and other cellular proliferative disorders involves having different chemotherapy treatment options for each condition.
An example of an important chemotherapeutic agent is the platinum-based compound cisplatin (cis-diamminedichloroplatinum (II); cis-Cl2(NH3)Pt). Cisplatin has a square planar geometry, with each of the two chloride groups (and likewise, each of the two amine groups) being adjacent, or cis, to each other.
Cisplatin was first approved for human use in the late 1970's and is prescribed for the treatment of a variety of tumours including germ-cell, advanced bladder carcinoma, adrenal cortex carcinoma, breast, testicular and ovarian cancer, head and neck carcinoma and lung carcinoma.
Cisplatin is active against proliferating or cancerous cells by binding to DNA and interfering with its repair mechanism, eventually leading to cell death. It is thought that the first step in the cellular process is that a molecule of water replaces one of the chloride ions of cisplatin. The resulting intermediate structure can then bind to a single nitrogen on a DNA nucleotide. Following that, the second chloride is also replaced by another water molecule and the platinum agent then binds to a second nucleotide. Binding studies of cisplatin with DNA have indicated a preference for nitrogen 7 on two adjacent guanines on the same strand. It also binds to adenine and across strands to a lesser extent.
The binding of cisplatin to DNA causes production of intrastrand cross-links and formation of DNA adducts. The adducts or cisplatin-DNA complexes attract the attention of DNA repair proteins which become irreversibly bound. The resulting distortion to the shape of the DNA by the binding of cisplatin prevents effective repair and hence, cell death.
Other well known chemotherapeutic agents include carboplatin, the taxanes such as paclitaxel, gemcitabine, 5-fluorouracil, methotrexate and the tetracyclines.
Patients undergoing cancer chemotherapy often have to contend with quite severe and debilitating side effects due to the toxicity of the active agents. Common side effects of chemotherapy are nausea and vomiting. Other side effects include temporary reduction in bone marrow function, numbness or tingling in hands or feet, changes in hearing, temporary taste alterations, loss of appetite, diarrhoea and allergic reactions.
Chemotherapy regimes are further complicated by the efficacy of currently available chemotherapeutic agents against various cancers or other tumour types sometimes being insufficient. For example, some cancer cells have developed natural tolerance against the therapeutic agents. Further, some therapeutic or prophylactic agents exert side effects, or can induce the development of tolerance in abnormally dividing cells during clinical use, leading to a situation in which certain tumour types become multiply drug resistant. Multidrug resistance thus remains a main complication of long-term successful tumour chemotherapy.
Accordingly there is a strong need to identify new, improved, better and/or alternative pharmaceutical compositions, agents and treatment regimes against chemosensitivity, mutated growth or proliferation of cells including cancer and related diseases. There is a further need for chemotherapeutic agents which address some of the undesirable side effects of known agents. There is also a need for different therapies to be available to physicians to combat the numerous and various types of cancers and to provide new options for treatment to address issues of tolerance of proliferating cells to the existing chemotherapeutic agents and treatment regimes. Agents which can act synergistically with other chemotherapeutics are highly sought after. Any beneficial effects which can be obtained with synergistic agents can reduce the amount and duration of traditional chemotherapeutic drugs or improve or restore chemoselectivity thereby providing safer administration and hopefully fewer or less sever side effects.
It is a preferred object of the present invention to provide pharmaceutical compositions and methods for the treatment, amelioration or prophylaxis of cancer and diseases associated with oxidant stress. The present invention also seeks to provide pharmaceutical compositions and methods for targeting neoplastic cells for treatment, which compositions and methods provide improved cell activity in terms of targeting function, improved delivery of toxic agents and/or improvement or restoration of chemosensitivity.